Regulatory cells, by virtue of their capacity to control the vigor of immune responses are essential to the maintenance of host homeostasis. Several types of CD4+ regulatory T cells exist some of which are induced in response to infectious challenge and some of which are judged as natural regulators (natural Treg). Natural Treg play a central role in the control of autoimmunity, a function that is associated with their capacity to recognize self-antigen. Whether or not they also recognize foreign antigens and the extent of their repertoire for such antigens remain unknown. We and others have shown that natural Treg also play a critical role in the outcome of microbial infections. Natural Treg help limit collateral tissue damage caused by vigorous antimicrobial immune responses. These cells can also limit the magnitude of effector responses which result in failure to adequately control infection. Furthermore, there are clear evidence that the efficiency of vaccines can also be hampered by the presence of natural Treg. A broad range of unicellular GI parasites, including Cryptosporidia, Giardia, Microsporidia, and Toxoplasma ssp., infect humans and together represent an important cause of morbidity and mortality worldwide. Our hypothesis is that these pathogens have evolved to manipulate Treg function to insure succesful infection. We are focusing our attention on 2 gastointestinal prozozoan parasites, Crypotosporidia and Microsporidia and are exploring the antigen specificity of natural Treg that accumulate at the site of infection as well as the conditions that favor their retention. We found that in the above mentioned models, natural Treg massively accumulate at sites of infection and modulate the intensity of effector immune responses.